tbuckley/cabot-search huggingface dataset:
Applying machine learning to consumer wearable data for the early detection of complications after pediatric appendectomy
Authors: Hassan M. K. Ghomrawi, Megan K. O’Brien, Michela Carter, Rebecca Macaluso, Rushmin Khazanchi, Michael Fanton, Christopher DeBoer, Samuel C. Linton, Suhail Zeineddin, J. Benjamin Pitt, Megan Bouchard, Angie Figueroa, Soyang Kwon, Jane L. Holl, Arun Jayaraman, Fizan Abdullah
Journal: npj Digital Medicine (2023)

When children are discharged from the hospital after surgery, their caregivers often rely on subjective assessments (e.g., appetite, fatigue) to monitor postoperative recovery as objective assessment tools are scarce at home. Such imprecise and one-dimensional evaluations can result in unwarranted emergency department visits or delayed care. To address this gap in postoperative monitoring, we evaluated the ability of a consumer-grade wearable device, Fitbit, which records multimodal data about daily physical activity, heart rate, and sleep, in detecting abnormal recovery early in children recovering after appendectomy. One hundred and sixty-two children, ages 3-17 years old, who underwent an appendectomy (86 complicated and 76 simple cases of appendicitis) wore a Fitbit device on their wrist for 21 days postoperatively. Abnormal recovery events (i.e., abnormal symptoms or confirmed postoperative complications) that arose during this period were gathered from medical records and patient reports. Fitbit-derived measures, as well as demographic and clinical characteristics, were used to train machine learning models to retrospectively detect abnormal recovery in the two days leading up to the event for patients with complicated and simple appendicitis. A balanced random forest classifier accurately detected 83% of these abnormal recovery days in complicated appendicitis and 70% of abnormal recovery days in simple appendicitis prior to the true report of a symptom/complication. These results support the development of machine learning algorithms to predict onset of abnormal symptoms and complications in children undergoing surgery, and the use of consumer wearables as monitoring tools for early detection of postoperative events.
Circulating Biomarkers Instead of Genotyping to Establish Metabolizer Phenotypes
Authors: Roman Tremmel, Ute Hofmann, Mathias Haag, Elke Schaeffeler, Matthias Schwab
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Pharmacogenomics (PGx) enables personalized treatment for the prediction of drug response and to avoid adverse drug reactions. Currently, PGx mainly relies on the genetic information of absorption, distribution, metabolism, and excretion (ADME) targets such as drug-metabolizing enzymes or transporters to predict differences in the patient's phenotype. However, there is evidence that the phenotype-genotype concordance is limited. Thus, we discuss different phenotyping strategies using exogenous xenobiotics (e.g., drug cocktails) or endogenous compounds for phenotype prediction. In particular, minimally invasive approaches focusing on liquid biopsies offer great potential to preemptively determine metabolic and transport capacities. Early studies indicate that ADME phenotyping using exosomes released from the liver is reliable. In addition, pharmacometric modeling and artificial intelligence improve phenotype prediction. However, further prospective studies are needed to demonstrate the clinical utility of individualized treatment based on phenotyping strategies, not only relying on genetics. The present review summarizes current knowledge and limitations.
Targeting Efferocytosis in Inflammaging
Authors: Ivan K.H. Poon, Kodi S. Ravichandran
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.
Phosphoproteomics of patient-derived xenografts identifies targets and markers associated with sensitivity and resistance to EGFR blockade in colorectal cancer
Authors: Robin Beekhof, Andrea Bertotti, Franziska Böttger, Valentina Vurchio, Francesca Cottino, Eugenia R. Zanella, Giorgia Migliardi, Marco Viviani, Elena Grassi, Barbara Lupo, Alex A. Henneman, Jaco C. Knol, Thang V. Pham, Richard de Goeij-de Haas, Sander R. Piersma, Mariette Labots, Henk M.W. Verheul, Livio Trusolino, Connie R. Jimenez
Journal: Science Translational Medicine (2023)

Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically and pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response to EGFR blockade and identify alternative drug targets to overcome resistance. Both the tyrosine and global phosphoproteome as well as the proteome harbored distinctive response signatures. We found that increased pathway activity related to mitogen-activated protein kinase (MAPK) inhibition and abundant tyrosine phosphorylation of cell junction proteins, such as CXADR and CLDN1/3, in sensitive tumors, whereas epithelial-mesenchymal transition and increased MAPK and AKT signaling were more prevalent in resistant tumors. Furthermore, the ranking of kinase activities in single samples confirmed the driver activity of ERBB2, EGFR, and MET in cetuximab-resistant tumors. This analysis also revealed high kinase activity of several members of the Src and ephrin kinase family in 2 CRC PDX models with genomically unexplained resistance. Inhibition of these hyperactive kinases, alone or in combination with cetuximab, resulted in growth inhibition of ex vivo PDX-derived organoids and in vivo PDXs. Together, these findings highlight the potential value of phosphoproteomics to improve our understanding of anti-EGFR treatment and response prediction in mCRC and bring to the forefront alternative drug targets in cetuximab-resistant tumors.
The Nocebo Effect
Authors: Luana Colloca
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Adverse nocebo responses can cause harm to patients and interfere with treatment adherence and effects in both clinic practice and clinical trials. Nocebo responses refer to negative outcomes to active medical treatments in clinical trials or practice that cannot be explained by the treatment's pharmacologic effects. Negative expectancies and nocebo effects are less known than placebo responses. Nocebo effects can be triggered by verbal suggestions, prior negative experiences, observation of others experiencing negative outcomes, and other contextual and environmental factors. As research advances over the years, mechanistic knowledge is accumulating on the neurobiological mechanisms of nocebo effects. This review summarizes studies on different facets of nocebo effects and responses and discusses clinical implications, ethical considerations, and future directions.
Apathy and Motivation: Biological Basis and Drug Treatment
Authors: Harry Costello, Masud Husain, Jonathan P. Roiser
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Apathy is a disabling syndrome associated with poor functional outcomes that is common across a broad range of neurological and psychiatric conditions. Currently, there are no established therapies specifically for the condition, and safe and effective treatments are urgently needed. Advances in the understanding of motivation and goal-directed behavior in humans and animals have shed light on the cognitive and neurobiological mechanisms contributing to apathy, providing an important foundation for the development of new treatments. Here, we review the cognitive components, neural circuitry, and pharmacology of apathy and motivation, highlighting converging evidence of shared transdiagnostic mechanisms. Though no pharmacological treatments have yet been licensed, we summarize trials of existing and novel compounds to date, identifying several promising candidates for clinical use and avenues of future drug development.
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation
Authors: Vladas Oleinikovas, Pablo Gainza, Thomas Ryckmans, Bernhard Fasching, Nicolas H. Thomä
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas.
Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury
Authors: Xiaojia Huang, Xianming Zhang, Narsa Machireddy, Colin E. Evans, Shawn D. Trewartha, Guochang Hu, Yun Fang, Gökhan M. Mutlu, David Wu, You-Yang Zhao
Journal: Science Translational Medicine (2023)

Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury and high mortality in aged mice after sepsis challenge were attributable to impaired endothelial regeneration and vascular repair. Genetic lineage tracing study showed that endothelial regeneration after sepsis-induced vascular injury was mediated by lung resident endothelial proliferation in young adult mice, whereas this intrinsic regenerative program was impaired in aged mice. Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of the FOXM1 gene driven by an endothelial cell (EC)–specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. Mechanistically, aging-induced Foxm1 promoter hypermethylation in mice, which could be inhibited by decitabine treatment, inhibited Foxm1 induction after sepsis challenge. In COVID-19 lung autopsy samples, FOXM1 was not induced in vascular ECs of elderly patients in their 80s, in contrast with middle-aged patients (aged 50 to 60 years). Thus, reactivation of FoxM1-mediated endothelial regeneration and vascular repair may represent a potential therapy for elderly patients with ARDS.
NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
Authors: Dong Yang, Bin Sun, Shirong Li, Wenwen Wei, Xiuyun Liu, Xiaoyue Cui, Xianning Zhang, Nan Liu, Lanzhen Yan, Yibin Deng, Xudong Zhao
Journal: Science Translational Medicine (2023)

Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16 INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.
Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination
Authors: Alexandra Suberi, Molly K. Grun, Tianyang Mao, Benjamin Israelow, Melanie Reschke, Julian Grundler, Laiba Akhtar, Teresa Lee, Kwangsoo Shin, Alexandra S. Piotrowski-Daspit, Robert J. Homer, Akiko Iwasaki, Hee-Won Suh, W. Mark Saltzman
Journal: Science Translational Medicine (2023)

An inhalable platform for messenger RNA (mRNA) therapeutics would enable minimally invasive and lung-targeted delivery for a host of pulmonary diseases. Development of lung-targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here, we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine- co -ester) (PACE) polyplexes for mRNA delivery using end-group modifications and polyethylene glycol. These polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for severe acute respiratory syndrome coronavirus 2 and found that intranasal vaccination with spike protein–encoding mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected susceptible mice from lethal viral challenge. Together, these results demonstrate the translational potential of PACE polyplexes for therapeutic delivery of mRNA to the lungs.
Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies
Authors: Jayastu Senapati, Warren C. Fiskus, Naval Daver, Nathaniel R. Wilson, Farhad Ravandi, Guillermo Garcia-Manero, Tapan Kadia, Courtney D. DiNardo, Elias Jabbour, Jan Burger, Nicholas J. Short, Yesid Alvarado, Nitin Jain, Lucia Masarova, Ghayas C. Issa, Wei Qiao, Joseph D. Khoury, Sherry Pierce, Darla Miller, Koji Sasaki, Marina Konopleva, Kapil N. Bhalla, Gautam Borthakur, Naveen Pemmaraju
Journal: Clinical Cancer Research (2023)

Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies.We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy.Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1-9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders.In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.
Clinical Inertia Among Outpatients With Heart Failure
Authors: Stanley A. Swat, Laura J. Helmkamp, Caroline Tietbohl, Jocelyn S. Thompson, Monica Fitzgerald, Colleen K. McIlvennan, Geoffrey Harger, P. Michael Ho, Faraz S. Ahmad, Tariq Ahmad, Peter Buttrick, Larry A. Allen
Journal: JACC Heart Failure (2023)
ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer CNS Metastasis
Authors: Ben Yi Tew, Alex J. Kalfa, Zeyi Yang, Kyle M. Hurth, Thomas Simon, Eric Abnoosian, Stephen T. Durant, Petra Hamerlik, Bodour Salhia
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Limited effective treatments are currently available for central nervous system (CNS) metastasis (CM). This is largely driven by the inability of current therapeutics to penetrate the blood brain barrier (BBB) and the lack of preclinical models for testing new therapies. Here we study the efficacy of AZD1390, a BBB penetrating ataxia-telangiectasia mutated inhibitor, as a radiosensitizer for breast cancer CM treatment. Experimental Design: Three patient-derived xenograft (PDX) tumors including 2 HER2+ and 1 triple-negative breast cancer harboring DNA damage response (DDR) gene mutations, were implanted subcutaneously in the flank of mice to assess tumor growth inhibition by AZD1390 combined with radiation. Animal survival was further assessed by implanting the best responding PDX model orthotopically in the brain. Results: Pretreatment with AZD1390 followed by radiation therapy inhibited growth of PDX tumors implanted in the flank, and improved survival in orthotopic models with average survival of 222 days compared with 123 days in controls. Administration of AZD1390 posttreatment for 21 days had no further benefits. While the combination therapy resulted in sustained tumor inhibition, sporadic regrowth was observed in some mice 50 to 100 days posttreatment in all models. Gene expression comparing these tumors with complete responders demonstrated changes in upregulation of oncogenic proteins, which are potential drivers of tumor growth after treatment. Conclusions: Our results demonstrate that AZD1390 effectively sensitizes breast cancer CM to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CM.
Re: Soumyajit Roy, Yilun Sun, Scott C. Morgan, et al. Effect of Prior Local Therapy on Response to First-line Androgen Receptor Axis Targeted Therapy in Metastatic Castrate-resistant Prostate Cancer: A Secondary Analysis of the COU-AA-302 Trial. Eur Urol 2023;83:571–9
Authors: Xiao Li, Zicheng Xu, Feng Qi
Journal: European Urology (2023)
Can quantifying the relative intensity of a person’s free-living physical activity predict how they respond to a physical activity intervention? Findings from the PACES RCT
Authors: Alex V Rowlands, Mark W Orme, Ben Maylor, Andrew Kingsnorth, Louisa Herring, Kamlesh Khunti, Melanie Davies, Tom Yates
Journal: British Journal of Sports Medicine (2023)

Objectives To determine whether quantifying both the absolute and relative intensity of accelerometer-assessed physical activity (PA) can inform PA interventions. We hypothesised that individuals whose free-living PA is at a low relative intensity are more likely to increase PA in response to an intervention, as they have spare physical capacity. Method We conducted a secondary data analysis of a 12-month randomised controlled trial, Physical Activity after Cardiac EventS, which was designed to increase PA but showed no improvement. Participants (N=239, 86% male; age 66.4 (9.7); control N=126, intervention N=113) wore accelerometers for 7 days and performed the incremental shuttle walk test (ISWT) at baseline and 12 months. PA intensity was expressed in absolute terms (intensity gradient) and relative to acceleration at maximal physical capacity (predicted from an individual’s maximal ISWT walking speed). PA outcomes were volume and absolute intensity gradient. Results At baseline, ISWT performance was positively correlated with PA volume (r=0.50, p&lt;0.001) and absolute intensity (r=0.50, p&lt;0.001), but negatively correlated with relative intensity (r=−0.13, p=0.025). Relative intensity of PA at baseline moderated the change in absolute intensity (p=0.017), but not volume, of PA postintervention. Low relative intensity at baseline was associated with increased absolute intensity gradient (+0.5 SD), while high relative intensity at baseline was associated with decreased absolute intensity gradient (−0.5 SD). Conclusion Those with low relative intensity of PA were more likely to increase their absolute PA intensity gradient in response to an intervention. Quantifying absolute and relative PA intensity of PA could improve enables personalisation of interventions.